Abstract

Neuronal activity, both intrinsically generated and sensory-evoked, is known to play an important role in the development of the brain. Sensory experiences continue to exert a strong influence on the functional connectivity of neuronal circuits, especially in the cerebral cortex, allowing for learning and adaptation to an ever changing environment. The visual system provides a convenient and well established model to study both development and experience-dependent plasticity of neuronal circuits. The aim of this thesis is to employ the mouse visual system to explore how neuronal activity influences the formation of brain circuits and mediates their experience-dependent modification later in life.
In the first part of this thesis (Chapter 2), I examined the role of retinal activity in the formation of topographic maps in a target region of retinal ganglion cells. It is generally assumed that in order to obtain such highly precise and ordered maps during development, spontaneous patterns of neuronal activity are crucial for the refinement of connections. Applying intrinsic signal imaging to mouse superior colliculus (SC), I confirmed this assumption by showing that functional connectivity is less precise in transgenic mice with disrupted patterns of retinal ganglion cell activity. In comparison to normal mice, visual stimuli activated larger, less defined regions in the SC in mice lacking early retinal waves. Surprisingly, I also found that the overall topographic organization was affected by the lack of correlated spiking in the retina. Although the rough retinotopic organization was maintained, the map showed substantial distortion, indicating that patterned retinal activity before eye-opening plays a more important role in topographic map formation than previously thought.
Later in development, sensory-evoked activity is equally influential in shaping functional connectivity, since altered sensory input induces strong changes in cortical circuitry. Closure of one eye for a few days (monocular deprivation, MD), for instance, substantially changes cortical responsiveness to the two eyes, shifting ocular dominance (OD) towards the non-deprived eye. This paradigm therefore provides a powerful model system for experience-dependent plasticity. In Chapter 3, I used intrinsic signal imaging to assess the magnitude of cortical responses evoked by stimulation of the two eyes in order to explore OD plasticity in mouse visual cortex. I confirmed recent, debated findings in demonstrating strong MD-induced plasticity in adult animals, which was mediated by partly different mechanisms than in juvenile mice. I also found that restoring binocular vision after MD led to full recovery of eye-specific responses at all ages. Interestingly, the prior experience of altered sensory input seemed to be somehow preserved in cortical circuits, such that subsequent cortical adaptation to the same experience was improved. A second MD resulted in much faster and more persistent OD shifts. This enhancement of plasticity was highly specific, as it was only observed for repeated deprivation of the same eye, indicating that a lasting trace was established in cortical connections by the initial experience.
In Chapter 4, I explored OD plasticity in greater detail by monitoring network activity at the level of individual neurons with in vivo two-photon imaging of calcium signals. Monitoring calcium transients associated with neuronal activity in up to hundred cells simultaneously, enabled me to examine MD-induced changes in the functional properties of each neuron independently. I found that, in general, deprived eye responses were weakened and non-deprived eye responses strengthened after MD in juvenile mice, as was expected from previous population response measurements. Neurons still dominated by deprived-eye inputs, however, did not lose their responsiveness, but rather exhibited enhanced responses following MD. This strongly suggests that homeostatic plasticity acted on these cells during deprivation and caused an up-scaling of their responsiveness, while neurons also receiving substantial input from the non-deprived eye shifted their responsiveness towards that eye. Both competitive and homeostatic processes therefore seem to operate during OD plasticity, depending on the distribution of functional inputs in individual cells.
In conclusion, the work presented in this thesis provides further insight into the role of activity-dependent mechanisms in determining and shaping functional connectivity in the brain.